Human cytomegalovirus (HCMV) causes severe disease in immunocompromised hosts, as well as in immunocompetent hosts. HCMV disease involves multiple organ systems, thus an essential feature of infections is the hematogenous dissemination of the virus. We recently provided evidence that monocytes and macrophages are principal cell types responsible for viral spread and life-long persistence. Our data suggest the following model for viral spread. Monocytes are infected in the blood, although not productively at the time of initial infection, and are induced by viral binding to cognate receptors to extravasate into various tissues. There they differentiate into long-lived macrophages, which support replication of the original virus, allowing for viral persistence in target organs. The ability to drive monocyte extravasation and monocyte-to-macrophage differentiation appears to be an essential function of HCMV. Our results are supported by clinical evidence, suggesting that the strategy of utilizing monocytes and macrophages for viral dissemination and persistence links HCMV infection to viral-mediated pathogenesis. How does HCMV influence monocyte function and force the infected monocyte to serve as Trojan Horses for hematogenous spread? Our new data show that viral binding is the key biological trigger for the changes in monocytes during infection. Viral binding to cognate cellular receptors on monocytes allows for the successful manipulation of the host-signaling pathways that serve as essential molecular determinants for viral dissemination. With the recent identification of HCMV receptors on fibroblasts (the epidermal growth factor receptor (EGFR) and cellular integrins), along with our new data showing that EGFR and integrins are bona fide receptors on monocytes that link viral binding to the unique functional changes in monocytes, we are now poised to decipher mechanisms by which HCMV manipulates monocyte function. We hypothesize that a unique combination of HCMV-mediated receptor/ligand interactions triggers distinct and specific changes in infected monocytes that promote viral persistence. To test our hypothesis, we will examine if HCMV glycoprotein binding to monocytes and macrophages functionally triggers biological changes;investigate the HCMV-signal-mediated transcriptome in monocytes and macrophages;and, determine the cellular mechanisms by which viral-mediated signaling promotes monocyte motility and survival. The results from this study will provide new insight into the mechanisms by which HCMV infection initiates unique molecular changes in infected monocytes and into the underlying causes of HCMV pathogenesis, as well as identify new potential targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus causes severe disease in congenitally infected infants, in transplant and AIDS patients, and is considered a strong risk factor for the development and severity of cardiovascular diseases. By defining the mechanisms of viral spread within the host and how the virus establishes life-long persistence, we provide fundamental insight into the underlying viral pathogenesis, as well as open up new potential targets for therapeutic or pharmacological intervention.